Bradykinin is known to produce intense pain when applied to the blister base in man, Kantor, et al., Proc. Soc. Exp. Biol. Med. 126: 505-507 (1967). In animals, its intraperitoneal injection induces writhing in rats and mice Collier, et al., Br. J. Pharmac. Chemoth. 32: 295-310 (1968); Dubinsky, et al., Prostaglandins 28(2): 241-252 (1984); and Loux, et al., Arzneim-Forsch Drug Res. 28(2): 1644-1647 (1978) and its intra-arterial injection causes pseudo affective responses in dogs and cats, Guzman, et al., Arch. Int. Pharmacodyn. 149 (3--3): 571-588 (1964); Juan, et al., Eur. J. Pharmaco. 65: 267-278 (1980); and Lim et al., Arch. Int. Pharmacodyn. 152(1-2): 25-58 (1964). The role of bradykinin in pain transmission is due in part to its direct effect on the pain receptors and in part to its indirect effect through the release of other mediators of pain and inflammation, Regoli, et al., Pharmacol. Rev. 32(1): 1-46 (1980). Essentially, most pain is associated, at least at the beginning, with inflammation at the peripheral receptor sites. Tissue injury causes the migration of polymorphonuclear leukocytes (PMN). Proteases released from PMN act on alpha 2-globulins to form bradykinin, which exerts both direct and indirect effects on pain transmission.
Bradykinin binds to the pain receptors at the nerve ending and causes the nerve to fire. The nerve impulses enter the spinal cord and cause the release of substance P which in turn amplifies the pain signals through an increase in nerve firing. Substance P also binds to the mast cells, stimulating histamine release, which causes further inflammation, thus enhancing the generation and propagation of pain impulses, Kantor, et al., Am. J. Med. 80 (S:3A): 3-9 (1986); and Shibata, et al., Jap. J. Pharmacol. 41: 427-429 (1986).
Bradykinin, at the same time, acts directly on the receptors of the capillary wall to increase the vascular permeability. Plasma exudation and increased leukocyte diapedesis follow. This allows inflammation to perpetuate and causes further release of mediators like prostaglandins, histamine and bradykinin, which all serve to further intensify the pain impulses, Yaksh, et al., in "Acetyl salicylic acid: New use for an old drug", ed. H. J. M. Barnett, J. Hirsh and J. F. Mustard, Raven Press, New York (1982) pp. 137-151.
Simultaneously bradykinin binds to mast cells, triggering the release of histamine, the ensuing additional inflammation and pain, and the cascade of reactions leading to the formation of more prostaglandins, Regoli, et al., Pharmacol. Rev. 32(1): 1-46 (1980). Thus, bradykinin, both by direct effects on cell membranes and indirect effects on the release of other mediators, triggers, transmits, and amplifies the pain impulses from the peripheral to the central sites. A bradykinin antagonist, therefore, would stop the pain signal before it reaches the central nervous system.